This proposal will explore the novel hypothesis that regulation of nuclear transport is altered in tumor cells, contributing to the development of apoptotic resistance and tumorigenesis. This hypothesis is based on our findings that tumor suppressor CC3/TIP30 has a novel cellular function as an inhibitor of nuclear transport. CC3 is a pro-apoptotic protein whose expression is frequently suppressed in aggressive human tumors. Recently, it was found that CCS id frequently mutated in various tumors, though the consequences of mutations for the cellular function of CCS remains to be established. CCS interacts with karyopherins of importin D family, NTF2 (Ran transport receptor) and nucleoporins. Tumor cells lacking CCS have a measurably higher rate of nuclear import, and are resistant to death signals. The ability of CCS to inhibit nuclear import is closely linked to its ability to promote apoptosis. Expression of CCS is induced after DNA damage in an evolutionary conserved manner, while silencing of CCS confers apoptotic resistance after DNA damage. High levels of CCS might inhibit the efficiency of DNA damage repair. The goal of this proposal is to understand how the inhibitory function of CC3/TIP30 in nuclear transport accounts for its pro-apoptotic and tumor-suppressing activities. To achieve this goal, it is necessary first to determine how interactions of CCS with the components of the nuclear transport machinery lead to the inhibition of the latter. Second, we will seek proof for the hypothesis that inhibition of nuclear transport by CCS plays a role in DNA damage responses, and examine the consequences of CCS deficiency in determining cell fate after DNA damage. Third, we will elucidate the molecular basis for the tumor- suppressing activity of CCS by exploring its effect on development of genomic instability and localization of relevant proteins with tumor suppressor activities. Overall, these studies will characterize the role of CCS in regulating nuclear transport under normal conditions and after DNA damage. They will determine how deregulation of nuclear transport contributes to tumorigenesis and apoptotic resistance. Examining tumor-specific alterations in nuclear transport is a novel approach in cancer research, and CCS provides a unique target for exploring this concept.